Despite enormous progress in understanding the pathophysiology of neoplasia, advanced forms of cancer remain recalcitrant to treatment. Though the basis for this failure is complex, one reason is that most tumors contain large, poorly vascularized areas that limit the efficacy of radiation and chemotherapeutic drugs (Jain, 1994)(Jain, 2001). The poorly vascularized regions are less sensitive to ionizing radiation because its cell-killing effects are dependent on oxygen; they are less sensitive to chemotherapeutic drugs because drug delivery to these regions is obviously suboptimal. As a cancer therapeutic agent must not leave significant clusters of viable cells within every lesion to achieve a clinically meaningful effect, the poorly vascularized regions of tumors represent a major obstacle to effective treatment.
One of the most important recent developments in tumor biology is the recognition that neoangiogenesis is essential for the growth of tumors to clinically meaningful sizes. What is less well-recognized is that this neoangiogenesis often does not keep pace with the growth of the neoplastic cells, resulting in large necrotic areas composed of dead or dying cells. For example, we found that each of 20 randomly selected liver metastases >1 cm3 in size contained relatively large regions of necrosis/apoptosis, in general constituting 25% to 75% of the tumor mass (FIG. 1). Cells adjacent to these necrotic areas are poorly vascularized and likely to be difficult to treat with conventional agents.
It has been recognized for half a century that anaerobic bacteria can selectively proliferate in the hypoxic regions of tumors (Parker, 1947)(Malmgren, 1955)(Mose, 1963)(Gericke, 1963)(Thiele, 1963)(Carey, 1967)(Kohwi, 1978)(Brown, 1998)(Fox, 1996)(Lemmon, 1997)(Sznol, 2000)(Low, 1999)(Clairmont, 2000)(Yazawa, 2000)(Yazawa, 2001)(Kimura, 1980). Clever strategies for potentially exploiting such bacteria for diagnostic and therapeutic purposes have been devised, though relatively little work in this area has recently taken place.